This application proposes to extend the Trial of Antioxidant Therapy of CVD in Women (Women's Antioxidant Cardiovascular Study ) for an additional 3.5 years of randomized treatment and follow-up. WACS is an ongoing randomized, double-blind, placebo-controlled, 2x2x2x2 factorial trial of vitamin C, vitamin E, beta-carotene, and folic acid/vitamin B6/vitamin B12 in the prevention of cardiovascular events among women aged > 40 years with preexisting cardiovascular disease or > 3 coronary risk factors. Its goal is to provide clear positive results or definitive null results on which to base clinical and public health recommendations about the use of antioxidants and B vitamins for the secondary prevention of cardiovascular disease. The current mean duration is 4.8 years in the antioxidant arm (n=8,171) and 2.6 years in the folic acid/vitamin B6/vitamin B12 arm (n=5,442). Based on a May 2000 review of the unblinded data, the trial's Data and Safety Monitoring Board unanimously recommended extending WACS beyond its scheduled termination in August 2002 in order to provide informative and conclusive results. With an additional 3.5 years of randomized treatment and follow-up, WACS will not only meet its original objectives but will also be able to assess the effects of antioxidant vitamins on individual endpoints and test whether antioxidant combinations are more effective than individual supplements alone, a valuable aim given conflicting results from single-agent trials. Archived blood samples (n=5,922) allow for the assessment of possible modifying effects of baseline vitamin and homocysteine levels. The WACS population, women at high risk of cardiovascular events, has been historically underrepresented in secondary prevention trials. Given its committed participants with high compliance, excellent follow-up, and willingness to continue, the trial is in an exceptional position to conclusively answer its central questions, as well as to evaluate the effects of homocysteine-lowering agents and antioxidant vitamins among women with diabetes, at less than $60/randomized participant/year in direct costs, a fraction of the usual cost of a secondary prevention trial. With the gaps in knowledge this study is intended to address and the certain intense interest in its findings by the medical, lay, and regulatory communities, the proposed extension of this trial in women is both important and timely.